Prevalence of fatigue functional and social impairment among patients with rheumatic diseases compared to patients without: A cross-sectional comparison

Rheumatic diseases (RD) are chronic diseases that significantly affect the lives of patients. Assessing health outcomes through a patient-reported outcome measurement information system (PROMIS) is essential for RD management. Moreover, these tend to be less favorable among individuals than among the rest of the population. This study aimed to compare PROMIS between RD patients and other patients. This cross sectional study was conducted in the year 2021. Information about patients with RD was obtained from the RD registry at King Saud University Medical City. Patients without RD were recruited from family medicine clinics. Patients were contacted electronically through WhatsApp© to complete the PROMIS surveys. We compared the individual PROMIS scores between the 2 groups using linear regression, adjusting for sex, nationality, marital status, education level, employment, family history of RD, income, and chronic comorbidities. There were 1024 individuals (512 with RD and 512 without RD). The most common RD was systemic lupus erythematosus (51.6%), followed by rheumatoid arthritis (44.3%). Individuals with RD reported significantly higher PROMIS T-scores for pain [β = 6.2; 95% confidence interval (CI) = 4.76, 7.71] and fatigue (β = 2.9; 95% CI = 1.37, 4.38) compared to those without RD. Moreover, RD individuals reported lower physical functioning (β = −5.4; 95% CI = −6.50, −4.24) and social interaction (β = −4.5; 95% CI = −5.73, −3.20). Patients with RD in Saudi Arabia, particularly those with systemic lupus erythematosus and rheumatoid arthritis, have significantly greater impairment in physical functioning and social interaction and report higher levels of fatigue and pain. Addressing and ameliorating these negative outcomes is necessary to improve quality of life.


Introduction
Rheumatic diseases (RD) are lifelong chronic illnesses that have been subject to increased prevalence in recent years. [1] The impact of these illnesses on patients extends far beyond the biomedical component, and affects their quality of life and wellness. [2][3][4] Many patients with RD experience pain, disability, and social impairments. [5] Biological, socioeconomic, and lifestyle choices can also contribute to the impairment in the quality of life of these individuals. [6] There is a growing need to appropriately quantify the impact of RD on patient quality of life. Such assessments usually focus on several domains of patients' lives, including psychological well-being, pain, functional disability, and social interaction, and use both generic and disease specific self-administrative tools. [7] These tools vary in validity, ease of use, and Medicine comprehensiveness. Among these tools is the patient-reported outcomes measurement information system (PROMIS), which was developed to assess different aspects of patient-reported outcomes (PRO), such as pain, fatigue, physical functioning, and social interaction. PROMIS is used in patients with RD in many international settings, and is considered a good tool for enhancing the understanding of different PROs in the clinical management of RD. [8] In Saudi Arabia, RD is a growing area of research interest. The prevalence of the most common RDs, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), was explored and reported at 2.2 cases per 1000 population and 19 cases per 100,000 population, respectively. [9,10] However, research on other RDs in Saudi Arabia is lacking. Recently, PROs research in patients with RD has increased in Saudi Arabia, with interesting findings compared to global reports. [11][12][13] However, aspects of pain, fatigue, physical functioning. and social interactions in the RD have not been sufficiently explored in the Saudi population. Expanding the knowledge on PROs in relation to RD is of great importance to the medical and clinical rheumatological communities to improve the management of RD towards a more holistic and patient-centered approach. Therefore, this study aimed to measure PROs among individuals with RD at one of the largest tertiary medical centers in Saudi Arabia and compare them with the PROs of patients without RD.

Study design and settings
This cross sectional study was conducted in 2021 at King Saud University Medical City (KSUMC), in accordance with the guidelines for strengthening observational studies in epidemiology. [14] KSUMC is a tertiary university hospital in Riyadh, whose beneficiaries are mostly the King Saud University faculty, students, and staff, along with their dependents, in addition to a few individuals referred from other governmental hospitals.

Study participants
As the purpose of our study was to compare PROs between individuals with RD and those without RD, we sampled equal proportions of patients with RD and those without RD from the KSUMC patient lists. Patients with RD were recruited from a clinical registry. This registry was first initiated in March 2020, and includes patients diagnosed with RD by a charitable association for RD, the Saudi Inflammatory Disease Patient Support Group, and specialized rheumatology clinics at KSUMC. Data collection for this registry is ongoing at the time of writing this manuscript. RD-free patients were recruited from a family medicine clinic. Patients mobile numbers were identified and randomly selected from the list. Patients were invited to participate in this study using text messages sent via WhatsApp © (WhatsApp LLC, USA). Electronic informed consent was obtained and self-administered questionnaires were sent to the participants.

Sample size
We estimated the sample size with reference to a study conducted by Nagaraja et al [8] , which assessed standardized PROMIS scores for individuals with rheumatological conditions. In that study, the mean T-scores were 40 (±8) for physical functioning, 58 (±10) for fatigue, 47 (±9) for ability to participate in social roles, and 55 (±8) for pain behavior. Considering these assumptions and assuming a desired precision of 1, the respective sample sizes required to achieve a confidence level of 95% would be 246 for estimating physical functioning PROMIS scores, 385 for fatigue PROMIS scores, 312 for the ability to participate in social roles PROMIS scores, and 246 for pain intensity PROMIS scores. Therefore, a minimum sample size of 385 participants per group was required to calculate PROMIS scores for all 4 domains. Assuming a response rate of 75%, the required sample size for each group is 514.

Study variables and measurements
2.4.1. Study outcomes. In this study, the outcome measures were the PROMIS scores for fatigue, physical functioning, pain, and social interaction. These were measured using questions from the 29-item PROMIS profile version 2.1, which assessed these 4 domains. [15] This tool consists of 8 items pertaining to fatigue, 10 items pertaining to physical functioning, 3 items pertaining to pain intensity, and 3 items pertaining to social interaction. The pain questions were scored on a 10-point Likert scale, while the other domains were scored on a 5-point Likert scale. For each domain, item scores were summed to create 4 separate composite scores. Finally, each of these composite scores was transformed into a T-score using the metric system website for PROMIS for each patient (https://www.assessmentcenter. net/ac_scoringservice). The score was calibrated using an average US score of 50 and a standard deviation of 10 as the reference group. The T-score was then categorized according to the PROMIS standardized cutoff points on the health measures website as normal, mild, moderate, and severe for fatigue, pain, and physical functioning, while social interaction was categorized as very high, high, average, low, and very low.

Study exposures
The survey also collected data on age, sex, marital status, nationality, education level, employment status, monthly household income in Saudi Riyals (SAR), family history of RD, and comorbidities.

Data collection
The data were collected electronically using Google Forms. Participation in the survey was voluntary. Patient identifiers were excluded from this study.

Ethical approval
The study was approved by the ethical approval of King Saud University Institutional Review Board No. E-20-4787), and information was managed with extreme confidentiality, without any participant's identifiers in the data collection form. In addition, the study complied with the ethical standards of the Declaration of Helsinki and all participants provided written informed consent.

Statistical analysis
Data analyses were performed using IBM statistical package for social sciences (SPSS) Statistics version 27.0 (IBM, Armonk,

Key points
• Patients with RD have significantly greater impairment in physical functioning and social interaction. • Patients with RD report higher levels of fatigability and pain. • Sex, nationality, marital status, level of education, employment, family history of RD, income, and chronic comorbidities were all confounding variables. NY). [16] We calculated the means and standard deviations for age and PROMIS scores were calculated, whereas frequencies and percentages were calculated for categorical measures. Categorical variables were compared between the 2 groups (patients with RD vs patients without RD) using chi-square tests, whereas continuous measures were compared using independent t tests. Finally, the association between RD status and PROMIS was assessed using linear regression analyses, in which each PROMIS sub score and t score were added as dependent variables, while RD status and covariates were added as independent variables. For these models, we controlled for sex, nationality, marital status, education level, employment, family history of RD, income, and chronic comorbidities. An alpha level of 0.05 was used for significance testing. Data was done by complete case analysis.

Results
A total of 1024 participants were included in the study, with 512 in each group. The response rates were 85% for patients with RD and 92.4% for patients without RD. For comorbidities of participants with or without RD, are available in supplementary material  (Table 1). Overall, the PROMIS sub-scores for pain and fatigue were significantly higher among patients with RD than among those without RD; the P value for independent t tests was < 0.001. Additionally, individuals without RD reported higher PROMIS sub-scores for physical functioning and social interaction (P < .001) ( Table 2). The percentage of "severe" levels of pain, fatigue, and physical functioning were greater among patients with RD (Fig. 1). Furthermore, the percentage of very low social interaction was greater among these patients, reflecting a poorer quality of life among patients with RD than among those without RD (Fig. 2).
Multivariate linear regression analyses revealed that subscores and T-scores for pain and fatigue were positively associated with RD, while sub-scores and T-scores for physical activity and social interaction were negatively associated with RD. More precisely, controlling for other covariates, RD was associated with 6.2 points increase in the T-score for pain [95% confidence  (Table 3).

Discussion
The burden of RD is reflected in PROs, which include fatigue, physical function, and social interaction. This finding was also observed in the present study. The findings of our study can be summarized as follows: First, PROMIS scores were significantly poorer among patients with RD than among those without RD. Second, even when controlling for potential confounding factors, RD was positively associated with higher PROMIS sub scores for pain and fatigue and negatively associated with higher PROMIS sub scores for physical functioning and social interaction, all of which suggest a significantly poorer quality of life among individuals with RD compared to the rest of the population. A recent large time series event study during the COVID-19 pandemic highlighted the prevalence of impairment in psychosocial and functional domains among patients with inflammatory arthritis living in Saudi Arabia. [12,13] However, it is unclear whether this degree of impairment differs significantly from that in the general population. Therefore, this significant difference was reflected in the present study.  Figure 1. Distribution of pain, fatigue and physical functioning PROMIS levels among rheumatic diseases (RD) patients and those without RD. PROMIS = patient-reported outcome measurement information system. www.md-journal.com SLE and RA comprise most patients with RD, which is consistent with the 2 most common inflammatory arthritis conditions in Saudi Arabia and globally. [12] Most of the patients were female, with significant differences in employment, income, and marital status, favoring the general population. This is particularly important, given the impact of social determinants on health and patient-reported outcomes. In support of this notion, a recent study by Izadi et al [17] showed that social disparity is associated with higher functional decline in patients with RA, which is partially mediated by disease activity.
As expected, the pain score was much higher in the patients with RD. Pain is a complex phenomenon, and the sources of pain can be multifactorial. [18] Obviously, Disease activity is a key factor. However, other centrally driven causes, such as fibromyalgia, which was more commonly observed in our cases, tended to be another important factor. [19] Pain also tends to be more prevalent in patients with co morbidities. Our data supports these findings. Identifying all potential factors associated with pain among patients with RD is paramount to understanding their pain, which significantly impairs their quality of life and likely affects other aspects of their quality of life, such as physical function, social interaction, and even mood. [13] In addition, one should keep in mind other contributing factor that may affect physical function and social interaction as the chronicity of rheumatic diseases that is Disease duration. [20,21] Fatigue is more prevalent in patients with RD than in the general population. In this study, Saudi patients with RD experienced significantly more fatigue, affecting almost 50% of the patients in the general population. Furthermore, almost 1-third of patients living with RDs experience moderate to severe fatigue, which is likely to affect their engagement with society and productivity at work. [22]    relationship between fatigue and social interaction scores, as well as the higher prevalence of impairment in social interaction among rheumatic patients compared to the general population.
In a qualitative assessment of the impact of fatigue on patients with SLE by Sterling et al [23] , work and family engagement were frequently found to be affected in patients with SLE. With a high burden of fatigue, impaired social interaction, and increased prevalence of pain and fibromyalgia, it is not surprising to see significant impairment in physical function. In our recent work on the impact of the COVID19 pandemic on the quality of life of patients with RD in Saudi Arabia, a very tight relationship between fatigue, physical function, and social interaction exists, such that 1 may influence the other. Physical function has also been associated with the development and worsening of multimorbidity, which is more prevalent among patients with RD. Hence, it is crucial to address exercises even in their simple and regular forms in patients suffering from RD, knowing that the benefits extend to various domains including mood, metabolism, pain, and even chronic inflammation.
This study was conducted to address the unmet need to understand the burden of RD, particularly RA and SLE, in patients compared with the general population. Both cases and controls were sampled from the same pool of populations, and the tools used to assess patient-reported outcomes were validated and universally used. However, this study has some limitations, including unmeasured confounders, such as disease activity or formal assessment of mood disorders. This must be considered during the interpretation of regression models. In conclusion, this study sheds light on the burden of RDs in patients compared with that in the general population. Patients with RDs have impaired physical function, social interactions, fatigue, and pain. These findings are consistent with global reports and highlight the need for population-based interventions to improve the quality of life.